4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds

Abstract

The invention relates to processes and intermediates for preparing compounds of formula I: where a, R1, and R3-6 are as defined in the specification, or a salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors.

Description

technical field

[0001] The present invention relates to 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds having activity as serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. The invention also relates to pharmaceutical compositions comprising the compounds, methods and intermediates for the preparation of the compounds, and methods of using the compounds in the treatment of pain disorders such as neuralgia and other diseases. Background technique

[0002] Pain is an unpleasant sensory and emotional experience associated with, or can be described in terms of, actual or potential tissue damage (International Association for the Study of Pain (IASP, Pain Terminology) . Chronic pain that lasts longer than acute pain or beyond the expected time for injury to heal (American Pain Society. "Pain Control in the Primary Care Setting." 2006: 15) . Neuralgia is pain initiated or caused by a primary lesion or dysfunction in the nervous system. Peripheral neuralgia ...

Examples

example

[0242] The following Preparations and Examples are provided to illustrate specific embodiments of the invention. However, these specific examples are not intended to limit the scope of the invention in any way unless otherwise indicated.

[0243] Unless otherwise indicated, the following abbreviations have the following meanings, and any other abbreviations used herein and not defined have their standard meanings:

[0244]

[0245] Any other abbreviations used herein but not defined have their generally accepted standard meanings. Unless otherwise noted, all materials such as reagents, starting materials and solvents were purchased from suppliers (such as Sigma-Aldrich, Fluka Riedel-de ) etc.) and used without further purification.

[0246] preparation 1

[0247] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate

[0248]

[0249] tert-Butyl 4-(2-carboxyphenyl)piperidine-1-carboxylate (5.0 g, 16 mmol, 1.0 eq.) was combined with THF (130 ...

example 1

[0260] 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine

[0261]

[0262] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate (2.1 g, 4.7 mmol, 1.0 eq.) was dissolved in MeCN (46 mL, 890 mmol) , and added to K 2 CO 3 (1.9g, 14mmol, 3.0eq.) and 2,4,6-trifluorophenol (1.0g, 7.0mmol, 1.5eq.). The mixture was shaken overnight at 50°C, then cooled to room temperature. The supernatant was mixed with K 2 CO 3 Separated from other solids. TFA (7 mL, 90 mmol, 20.0 eq.) was added to the supernatant and the mixture was shaken at room temperature overnight. The solution was then concentrated to obtain a crude residue. The residue was dissolved in 5.0 mL of 1:1 AcOH / H 2 O, then redissolved in 2.0 mL of AcOH, filtered and purified by preparative HPLC to afford the title compound as a TFA salt (1.3 g, 97.5% purity). MS m / z: C 18 h 18 f 3 [M+H] of NO + The calculated value is 322.13; the experimental value is 322.2.

[0263] 1 H NMR (CDCl 3 ) ...

example 2

[0275] 4-[2-(2,6-Difluorophenoxymethyl)phenyl]piperidine

[0276]

[0277] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate (225 mg, 505 μmol, 1.0 eq.) was dissolved in MeCN (5.0 mL, 97 mmol), and add to K 2 CO 3 (210mg, 1.5mmol, 3.0eq.) and 2,6-difluorophenol (98mg, 760μmol, 1.5eq.). The mixture was shaken overnight at 50°C, then cooled to room temperature. The supernatant was mixed with K 2 CO 3 Separated from other solids.

[0278] TFA (800 μL, 10 mmol, 20.0 eq.) was added to the supernatant and the mixture was shaken overnight at room temperature. The solution was then concentrated to obtain a crude residue. The residue was dissolved in 1.5 mL of 1:1 AcOH / H 2 O, then redissolved in 0.3 mL AcOH, filtered and purified by preparative HPLC to afford the title compound (115 mg, 95% purity) as a TFA salt. MS m / z: C 18 h 19 f 2 [M+H] of NO + The calculated value is 304.14; the experimental value is 304.2.

[0279] The following NMR d...

technical field

[0001] The present invention relates to 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds having activity as serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. The invention also relates to pharmaceutical compositions comprising the compounds, methods and intermediates for the preparation of the compounds, and methods of using the compounds in the treatment of pain disorders such as neuralgia and other diseases. Background technique

[0002] Pain is an unpleasant sensory and emotional experience associated with, or can be described in terms of, actual or potential tissue damage (International Association for the Study of Pain (IASP, Pain Terminology) . Chronic pain that lasts longer than acute pain or beyond the expected time for injury to heal (American Pain Society. "Pain Control in the Primary Care Setting." 2006: 15) . Neuralgia is pain initiated or caused by a primary lesion or dysfunction in the nervous system. Peripheral neuralgia ...

Examples

example

[0242] The following Preparations and Examples are provided to illustrate specific embodiments of the invention. However, these specific examples are not intended to limit the scope of the invention in any way unless otherwise indicated.

[0243] Unless otherwise indicated, the following abbreviations have the following meanings, and any other abbreviations used herein and not defined have their standard meanings:

[0244]

[0245] Any other abbreviations used herein but not defined have their generally accepted standard meanings. Unless otherwise noted, all materials such as reagents, starting materials and solvents were purchased from suppliers (such as Sigma-Aldrich, Fluka Riedel-de ) etc.) and used without further purification.

[0246] preparation 1

[0247] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate

[0248]

[0249] tert-Butyl 4-(2-carboxyphenyl)piperidine-1-carboxylate (5.0 g, 16 mmol, 1.0 eq.) was combined with THF (130 ...

example 1

[0260] 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine

[0261]

[0262] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate (2.1 g, 4.7 mmol, 1.0 eq.) was dissolved in MeCN (46 mL, 890 mmol) , and added to K 2 CO 3 (1.9g, 14mmol, 3.0eq.) and 2,4,6-trifluorophenol (1.0g, 7.0mmol, 1.5eq.). The mixture was shaken overnight at 50°C, then cooled to room temperature. The supernatant was mixed with K 2 CO 3 Separated from other solids. TFA (7 mL, 90 mmol, 20.0 eq.) was added to the supernatant and the mixture was shaken at room temperature overnight. The solution was then concentrated to obtain a crude residue. The residue was dissolved in 5.0 mL of 1:1 AcOH / H 2 O, then redissolved in 2.0 mL of AcOH, filtered and purified by preparative HPLC to afford the title compound as a TFA salt (1.3 g, 97.5% purity). MS m / z: C 18 h 18 f 3 [M+H] of NO + The calculated value is 322.13; the experimental value is 322.2.

[0263] 1 H NMR (CDCl 3 ) ...

example 2

[0275] 4-[2-(2,6-Difluorophenoxymethyl)phenyl]piperidine

[0276]

[0277] tert-butyl 4-[2-(toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylate (225 mg, 505 μmol, 1.0 eq.) was dissolved in MeCN (5.0 mL, 97 mmol), and add to K 2 CO 3 (210mg, 1.5mmol, 3.0eq.) and 2,6-difluorophenol (98mg, 760μmol, 1.5eq.). The mixture was shaken overnight at 50°C, then cooled to room temperature. The supernatant was mixed with K 2 CO 3 Separated from other solids.

[0278] TFA (800 μL, 10 mmol, 20.0 eq.) was added to the supernatant and the mixture was shaken overnight at room temperature. The solution was then concentrated to obtain a crude residue. The residue was dissolved in 1.5 mL of 1:1 AcOH / H 2 O, then redissolved in 0.3 mL AcOH, filtered and purified by preparative HPLC to afford the title compound (115 mg, 95% purity) as a TFA salt. MS m / z: C 18 h 19 f 2 [M+H] of NO + The calculated value is 304.14; the experimental value is 304.2.

[0279] The following NMR d...

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